Self-Protection against Gliotoxin—A Component of the Gliotoxin Biosynthetic Cluster, GliT, Completely Protects Aspergillus fumigatus Against Exogenous Gliotoxin

PLoS Pathogens

Gary W. Jones¹  Stephen Carberry¹  Kevin Kavanagh²  Hubertus Haas²  Jennifer O'Brien²  John Stephens²  Markus Schrettl²  Aine Nolan²  Orla Fenelon³  Sean Doyle³ 

[1] Biocenter-Division of Molecular Biology, Innsbruck Medical University, Innsbruck, Austria;Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland;Department of Chemistry, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland

关键词: Aspergillus fumigatus;    Aspergillus nidulans;    Saccharomyces cerevisiae;    Biosynthesis;    Fungal genetics;    Fungi;    Liquid chromatography-mass spectrometry;    Metabolites;   

DOI  :  10.1371/journal.ppat.1000952

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Gliotoxin, and other related molecules, are encoded by multi-gene clusters and biosynthesized by fungi using non-ribosomal biosynthetic mechanisms. Almost universally described in terms of its toxicity towards mammalian cells, gliotoxin has come to be considered as a component of the virulence arsenal of Aspergillus fumigatus. Here we show that deletion of a single gene, gliT, in the gliotoxin biosynthetic cluster of two A. fumigatus strains, rendered the organism highly sensitive to exogenous gliotoxin and completely disrupted gliotoxin secretion. Addition of glutathione to both A. fumigatus ΔgliT strains relieved gliotoxin inhibition. Moreover, expression of gliT appears to be independently regulated compared to all other cluster components and is up-regulated by exogenous gliotoxin presence, at both the transcript and protein level. Upon gliotoxin exposure, gliT is also expressed in A. fumigatus ΔgliZ, which cannot express any other genes in the gliotoxin biosynthetic cluster, indicating that gliT is primarily responsible for protecting this strain against exogenous gliotoxin. GliT exhibits a gliotoxin reductase activity up to 9 µM gliotoxin and appears to prevent irreversible depletion of intracellular glutathione stores by reduction of the oxidized form of gliotoxin. Cross-species resistance to exogenous gliotoxin is acquired by A. nidulans and Saccharomyces cerevisiae, respectively, when transformed with gliT. We hypothesise that the primary role of gliotoxin may be as an antioxidant and that in addition to GliT functionality, gliotoxin secretion may be a component of an auto-protective mechanism, deployed by A. fumigatus to protect itself against this potent biomolecule.

【 授权许可】

CC BY